Neurodegenerative disease is the general term for a group of diseases of unknown cause resulting in neural disorders at a specific site. More specifically, examples of degenerative diseases of the cerebrum include Alzheimer's disease, and Pick's disease, examples of degenerative diseases of the cerebral basal ganglia include Parkinson's disease and Huntington's disease, examples of degenerative diseases of the cerebellum include spinocerebellar atrophy, and degenerative diseases of the spinal cord include amyotrophic lateral sclerosis.
Since the cause of these neurodegenerative diseases is unknown, it is difficult to treat them with etiogenic therapy, making it necessary to rely upon nosotropic therapy.
For example, although all of the drugs currently approved for use as therapeutic agents of Alzheimer's disease are acetylcholine nervous system activators, they are nosotropic therapeutic agents developed on the basis of the pathological finding that the acetylcholine nervous system is significantly impaired in Alzheimer's disease patients. In addition, in actual Alzheimer's dementia, it has been demonstrated that the acetylcholine nervous system is not the only system that is impaired, and with respect to this point as well, there thought to be limitations on the effects of acetylcholine nervous system activators.
However, due to the recent progress in disease research at the molecular level, it has been demonstrated that many neurodegenerative diseases share a common characteristic in that neuropathy/cell death is induced by the polymerization and accumulation within the cell of abnormal proteins unique to each disease.
For example, in the brain of an Alzheimer's disease patient, amyloid-like extracellular deposits referred to as senile plaque, and fibrous compounds composed mainly of phosphorylated tau protein (neurofibrillary tangle), are observed in parallel with pathological condition. The major component of senile plaque is an insoluble protein adopting a β sheet structure composed of 40 to 43 amino acid residues referred to as amyloid β protein (Aβ). This protein has been demonstrated to be formed as a result of cleavage in the vicinity of a membrane penetrating region of a membrane protein referred to as amyloid precursor protein (APP). As a result of etiogenic gene analysis of hereditary Alzheimer's disease, since it was found that a mutation occurs in the APP gene itself resulting in increased production of Aβ, or production of Aβ increases due to mutation of the presenilin gene, a different etiogenic gene, and that Aβ extracted from the body or synthesized artificially exhibits toxicity on nerve cells, the idea that the mechanism of occurrence of Alzheimer's disease involves excessively produced Aβ becoming insoluble causing it to be deposited in nerve cells and demonstrate toxicity which in turn causes degeneration is considered to be the most promising.
In addition to Alzheimer's disease, in disorders such as Huntington's disease, spinal and bulbar atrophy, Machado-Joseph's disease, denatorubropallidoluysian atrophy, the accumulation and aggregation of polyglutamine formed due to the elongation of a CAG repeat within the gene, and in prion diseases such as Creutzfeldt-Jakob's disease, the accumulation and aggregation of abnormal protein caused by structural conversion of normal prion protein by some unknown cause, have been determined to be the cause of neuropathy/cell death in each of these diseases. Moreover, in Parkinson's disease and Lewy body disease, the accumulation and deposition of a protein known as α-cynucrein, and in amyotrophic lateral sclerosis, the accumulation and aggregation of a mutant superoxide dismutase, have been indicated has having the potential to cause neuropathy/cell death. In addition, among these, although prion protein and α-cynucrein adopt a β sheet structure in the same manner as Aβ, this has been determined to function as the trigger that causes aggregation and deposition.
Thus, if it were possible to produce a model that expresses a pathological state similar to that of human disease by making abnormal proteins thought to cause these neurodegenerative diseases present in excess in the body of an animal, that model could be considered to be extremely useful in terms of developing etiogenic therapy for neurodegenerative diseases.
Attempts have previously been made to produce an animal model of Alzheimer's disease either by producing Aβ in excess in an animal body by transgenic mouse technology, or by inducing a disorder by directly injecting Aβ into the brain of a normal animal. For example, decreased learning and memory ability has been reported by implanting a miniaturized osmotic pressure pump beneath the skin of the back of a normal rat for the purpose of continuous infusion of β protein into the ventricle, (Neuroscience Letters, Vol. 170, pp. 63-66, 1994). This β protein ventricular infusion model is the most suitable as a system for evaluating Alzheimer's disease therapeutic agents used for the purpose of etiogenic therapy.
On the other hand, prostaglandin (PG) compounds are known to have various physiological activities, including potent platelet aggregation inhibitory action, vasodilation and its accompanying blood pressure lowering action, gastric acid secretion inhibitory action, smooth muscle contractile action, cell protective action and diuretic action. Numerous attempts have been made to develop natural PG present in the body, or PG derivatives synthesized in the form of their agonists, as pharmaceuticals based on these physiological activities, and some of those attempts have lead to pharmaceuticals that have actually been marketed commercially.
Among PG, natural prostacyclins are locally acting hormones produced primarily in the vascular endothelium in the body, and attempts have been made to use them directly as pharmaceuticals by utilizing their potent physiological activity such as platelet aggregation inhibitory action and vasodilatory action (P. J. Lewis, J. O. Grady, Clinical Pharmacology of Prostaglandin). However, since natural prostacyclins have an enol-ether bond within their molecules that is susceptible to hydrolysis, they have the problem of being easily deactivated under neutral or acidic conditions, thereby preventing them from being preferable compounds for use as pharmaceuticals due to their chemical instability. Thus, research has been conducted on the synthesis of chemically stable synthetic prostacyclin derivatives that exhibit similar activity to that of natural prostaglandins (Synthesis, 1984, 449, Japanese Unexamined Patent Publication No. 61-129146). 9(O)-methano-Δ6(9α)-prostaglandin I1 (isocarbocyclines) has been synthesized that adequately satisfies chemical stability by substituting methine groups (—CH═) for the oxygen atoms at the 6th and 9th positions of prostacycline (Japanese Unexamined Patent Publication No. 59-210044), and this compound has demonstrated potent platelet aggregation inhibitory action, vasodilatory blood pressure lowering action and other biological activities comparable to natural prostaglandins (Japanese Unexamined Patent Publication No. 59-210044, Japanese Unexamined Patent Publication No. 61-197518).
In the past however, development of PGs as pharmaceuticals has primarily taken place in the obstetrics and gynecology, cardiovascular and gastrointestinal fields. In addition, they have also been indicated as being useful as oral therapeutic agents for diabetes (Japanese Unexamined Patent Publication No. 2-167227). However, PG compounds also have the potential for being useful as pharmaceuticals in the field of neurology and psychiatry.
Namely, PGD2, PGE1 or the isocarbacycline derivative mentioned above has been shown to demonstrate cerebral protective action on animals in a hypoxic state (Japanese Unexamined Patent Publication No. 60-146826, Japanese Unexamined Patent Publication No. 4-187637, Brain Research, Vol. 769, pp. 321-328, 1997).
In addition, it has also been reported that PGD2, PGE1, PGE2 or PGF2α has a process extension promoting action on neuroblastoma cells (Bulletin of the Japanese Society for Neurochemistry, Vol. 24, 376, 1985; Japanese Pharmacology and Therapeutics, Vol. 21, 37, 1993), that PGI2 and PGE2 have a protective action on primary cultured nerve cells (Neuroscience Letters, Vol. 160, 106, 1993); Brain Research, Vol. 663, 237, 1994), and that PGD2, PGJ2 and so forth have an action that promotes production of nerve growth factor (Japanese Unexamined Patent Publication No. 7-291867).
However, none of these reports specifically indicate the potential for PGs being able to be used as therapeutic agents for neurodegenerative diseases.
However, in the case of attempting to develop a pharmaceutical in the field of neurology and psychiatry, there are problems resulting from the diverse actions possessed by PGs as described above causing adverse side effects, and in order to solve these problems, it is necessary to obtain a compound that acts as specifically as possible on the brain and nervous system. In addition, another problem is the vascular system of the brain restricting the permeability of certain compounds due to the presence of the so-called blood-brain barrier, and in order to develop a PG as a pharmaceutical, it is necessary to enhance the permeability of that PG through the blood-brain barrier.
Therefore, as a result of conducting an in vitro autoradiographic evaluation in a large coronal section of the cerebral hemisphere of Japanese monkeys using a labeled prostacyclin derivative ([3H]iloprost-Schering), the inventors of the present invention found prostacyclin bonding sites in the striatum, amygdala nucleous, hippocampus and a portion of the cerebral cortex. In addition, the [3H]iloprost binding sites found here differed from the binding sites of [3H]PGE2, and PGE2 and PGE1 were determined to recognize the same receptors. In platelets, iloprost binding sites also react with PGE1, and are known to be completely different from PGE2 receptors.
During the course of the above research, a novel PGI2 receptor has been determined to exist in the central nervous system (Neuroscience, Vol. 65, pp. 493-503, 1995), and certain of the inventors of the present invention found several types of isocarbacycline derivatives that function as specific ligands of this novel PGI2 receptor present in the central nervous system (Japanese Unexamined Patent Publication No. 8-245498, Japanese Unexamined Patent Publication No. 10-87608, Japanese Unexamined Patent Publication No. 10-10610, Japanese Unexamined Patent Publication No. 11-5764 and Journal of Neurochemistry, Vol. 72, pp. 2583-2592, 1999). These isocarbacycline derivatives have demonstrated protective action on cultured nerve cells and animal cerebral nerve cells in a hypoxic state (EP-911314).
On the other hand, it has been reported that stability can be improved by formulating PGE1, PGA1 or the above isocarbacycline derivative as a lipid microshere preparation (Japanese Unexamined Patent Publication No. 58-222014, Japanese Unexamined Patent Publication No. 59-141518 and Japanese Unexamined Patent Publication No. 61-289034). Moreover, penetration to the brain when administered into the blood has been shown to increase by formulating the methyl ester of the isocarbacycline derivative as a lipid emulsion (J. Pharm. Pharmacol., Vol. 48, pp. 1016-1022, 1996).